Thesis
Novel insights into TLR4:TLR3 crosstalk in response to TLR4 specific ultrapure lipopolysaccharide (LPS) from highly pathogenic Escherichia coli 0111:B4 in murine microglia
Master of Science (M.S.), Drexel University
Apr 2021
DOI:
https://doi.org/10.17918/00000574
Abstract
Lipopolysaccharide (LPS), the major component of gram-negative bacterial plasma membranes, is a potent endotoxin that triggers Toll-like receptor 4 (TLR4) dependent downstream activation, leading to the production of proinflammatory cytokines and type I interferons (IFN). TLR4 is unique amongst the TLR superfamily in that it is capable of signaling via both Mal/MyD88 adaptors from the plasma membrane and TRIF adaptor from endosomes. Increased LPS serum levels have been implicated in a plethora of neuroinflammatory and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, as well as septic shock in extreme endotoxemia. TLR3 senses viral dsRNA and signals solely via the TRIF adaptor pathway, generating an antiviral state. LPS has been shown to upregulate TLR3 expression at mRNA and protein levels. However, the impact of LPS stimulation on TLR3 activation remains unexplored. Considering the roles of TLR4 and TLR3 in bacterial and viral infections, respectively, and their emerging implications in neuroinflammatory and neurodegenerative diseases, we sought to determine the effect of TLR4 specific ultrapure LPS-EB from highly pathogenic E. coli on TLR3 activation in murine microglia. We investigated TLR3 activation at residue Y759 and proinflammatory effectors in response to LPS-EB ultrapure in WT, TLR4, TRIF, and Mal/MyD88 functional knockout microglia. Our results demonstrate a previously unrecognized TLR4/Mal/MyD88-dependent TLR3 activation in response to LPS-EB ultrapure in murine microglia. This data highlights novel TLR4:TLR3 crosstalk in murine microglia with implications on i. Bacterial and viral co-infections, ii. Leaky gut mediated chronic inflammatory diseases, iii. Septic shock, iv. Cancer.
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Details
- Title
- Novel insights into TLR4:TLR3 crosstalk in response to TLR4 specific ultrapure lipopolysaccharide (LPS) from highly pathogenic Escherichia coli 0111:B4 in murine microglia
- Creators
- Brett Arthur LaBier
- Contributors
- Sonia Navas-Martin (Advisor)Joris Beld (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 86 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991014972849204721